查找使用阿拉丁产品的科研文献

Lupeol-3-carbamate Derivatives: Synthesis and Biological Evaluation as Potential Antitumor Agents

Shuang Tian,Yinxu Zhao,Siqi Deng,Liman Hou,Juan Song,Ming Wang,Ming Bu

In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50= 5.39~9.43 μM) was exhibited by compound3iagainst all three tumor cell lines. In addition, a salt reaction was performed on compound3k(IC50= 13.98 μM) and it was observed that the anti-proliferative activity and water solubility of compound3k·CH3I(IC50= 3.13 μM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound3k·CH3Ithrough the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.

Microglia Autophagy Mediated by TMEM166 Promotes Ischemic Stroke Secondary to Carotid Artery Stenosis

Li Li,Paul R. Krafft,Na Zeng,Ranran Duan,Xiang Qi,Anwen Shao,Fushan Xue,John H. Zhang

Ischemic stroke can be a serious complication of selective carotid endarterectomy (CEA) in patients with carotid artery stenosis (CAS). The underlying risk factors and mechanisms of these postoperative strokes are not completely understood. Our previous study showed that TMEM166-induced neuronal autophagy is involved in the development of secondary brain injury following cerebral ischemia-reperfusion injury in rats. This current study aimed to investigate the role of TMEM166 in ischemic stroke following CEA. In the clinical part of this study, the quantitative analysis demonstrated circulating TMEM166, interleukin 6 (IL-6), and C-reactive protein (CRP) levels were significantly elevated in patients who suffered an ischemic stroke after CEA compared to those who did not. Furthermore, non-survivors exhibited higher levels of these proteins than survivors. In the preclinical part of this study, a middle cerebral artery occlusion (MCAO) model was implemented following CAS simulation in TMEM166 -/- mice. We found TMEM166 expression was positively correlated with the degree of ischemic brain injury. Ad5-TMEM166 transfection aggravated ischemic brain injury by inducing microglial autophagy activation and release of inflammatory cytokines. Accordingly, TMEM166 deficiency reduced brain inflammation and inhibited excessive microglial autophagy through the mammalian target of rapamycin (mTOR) pathway. These findings suggest that TMEM166 may play a key role in the development of ischemic injury after CEA and may serve as a biomarker for risk assessment of postoperative ischemic stroke.

Enhanced therapeutic effects of ginseng-derived exosome-like nanoparticles loaded hyaluronic acid injectable hydrogels for breast tumor treatment

Yawen Yu,XinLiu Duan,Xiaorong Wang,Mingyan Yang,Ling Weng,Dalei Li,Teng Liu,Baifang Gong,Zhixia Wang,Huaying Fan

Ginseng-derived exosome-like nanoparticles (GENs) have been considered as new candidates for tumor therapy. However, maintaining the retention and stability of exosomes in vivo is a major challenge in clinical application of GENs. Here, we prepared hydrogels using modified hyaluronic acid (HA) and carboxymethyl chitosan (CMCS). We investigated whether the combination of GENs with hydrogels could improve the stability of GENs and enhance their retention in tumor tissues, thereby enhancing their tumor therapeutic effect. In vitro experiments showed that hydrogels significantly increased the uptake of GENs by cells and increased tumor apoptosis rate. In vivo experiments showed that hydrogels significantly increased the retention of GENs in tumor tissues and improved the antitumor ability of GENs. Meanwhile, we evaluated the anti-tumor mechanism of GENs. The results showed that GENs and GENs@Hydrogels induced 4T1 cell apoptosis through the PTEN/PI3K/Akt/mTOR pathway and caspase-dependent pathway. In addition, GENs and GENs@Hydrogels down-regulate PD-L1 level in tumor tissues, up-regulate MHC-I level, and increase the abundance of CD8+T cells, which have immune regulation ability. In conclusion, GENs@Hydrogels has been shown to be a successful candidate for the treatment of breast cancer (BC) with its promising potential to modulate immunity and inhibit tumor progression.

Synergistic Effects of Ginsenoside Rb3 and Rc From Panax notoginseng Leaf on Alleviating Neuroinflammation via PACAP in Depression

Shu-zhen Ran,Rui Peng,Qin-wan Guo,Li-juan Ma,Jian-bo Wan,Jun-qing Huang,Zi-ying Wang,Gang Chen

Panax notoginseng Leaf (PNL), an edible-medicinal botanical resource, shows potential as functional ingredients for alleviating depression, owing to their unique saponin composition. This study investigates the regulatory effects of PNL-derived saponins on pituitary adenylate cyclase-activating polypeptide (PACAP) and their related antidepressant mechanisms. Our findings demonstrate that PNL supplementation significantly alleviates depressive-like behaviors. Mechanistically, PNL upregulates PACAP expression in the hippocampus and activates the downstream CREB and mTOR signaling pathways, leading to increased expression of synaptic plasticity markers, including BDNF and PSD95, while concurrently inhibiting microglial activation and the production of pro-inflammatory cytokines. Among the major saponins in PNL, ginsenosides Rb3 and Rc were found to synergistically enhance PACAP expression in the cultured PC12 cells. These results underscore the potential of PNL for novel functional food ingredients, highlighting the antidepressant synergism of its naturally occurring ginsenosides (Rb3/Rc), and provide a natural antidepressant strategy.

Apios americana Medik flowers polysaccharide (AFP-2) attenuates H2O2 induced neurotoxicity in PC12 cells

Qiang Chu,Meng Chen,Dongxiao Song,Xixi Li,Yunyun Yang,Zihuan Zheng,Yonglu Li,Yangyang Liu,Lushuang Yu,Zheng Hua,Xiaodong Zheng

Oxidative stress is a critical cause for the progression of neurodegenerative diseases, indicating that screening natural antioxidant and pharmacological targeting of mechanism need more attention. Natural plant polysaccharides are the primary group of natural antioxidants showing mighty antioxidant activity. Therefore, a polysaccharide (AFP-2) from flowers of Apios americana Medik was isolated, purified and characterized. Then, a H 2 O 2 -induced PC12 cells oxidative stress model was established to investigate the neuroprotective role of AFP-2 and to clarify the potential mechanism of action against H 2 O 2 -induced neurotoxicity. It was found that AFP-2 reduced ROS production and mitochondrial damage caused by hydrogen peroxide in PC12 cells. In addition, data from transmission electron microscope and western blot displayed that AFP-2 significantly activated autophagy in PC12 cells via Akt-mTOR pathway. These results together qualify AFP-2 as an interesting natural polysaccharide worth further investigation as a neuroprotective agent.

Synergistic Induction of Apoptosis by Apocytochrome C and Sodium Aescinate Is Mediated by Excessive Autophagy via the AKT-mTOR-TFEB Signaling Axis

Jia-Wei Sun,Yin-Kang Chen,Liang Ji,Jian Zhao,Fu-Jun Wang

Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy. Summary This study reveals a novel strategy to combat cancer by repurposing an endogenous anti-apoptotic protein into a potent therapeutic agent. We demonstrate that apocytochrome C (APO-Cyt C), when combined with the natural compound sodium aescinate (SA), triggers cancer cell death through excessive autophagy rather than conventional apoptotic pathways. The discovery that this combination induces lethal autophagy by synergistically targeting both mTOR signaling and lysosomal function provides important insights for overcoming drug resistance. These findings highlight the promising therapeutic potential of combining mTOR inhibitors with lysosome-targeting saponins, establishing a new paradigm for cancer treatment through coordinated regulation of autophagic processes.

Salvianolic Acid B Enhances Motor Function Recovery after Spinal Cord Injury in Association with AKT/mTOR/HIF-1α Pathway Activation and Angiogenesis

Jiange Yao,Yingfeng Chen,Fengjun Pan,Susu Zhang

Salidroside alleviates senile osteoporosis in SAMP8 mice by inhibiting the ferroptosis of bone marrow stromal cells via PI3K/AKT/mTOR signaling pathway

Zhun Li,Sixia Yang,Wei Liu,Long Ling,Hailan Hu,Yanming Cao,Shouyu Xiang

Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.

Enhancement of osteoporotic bone regeneration by strontium-substituted 45S5 bioglass via time-dependent modulation of autophagy and the Akt/mTOR signaling pathway

Xinran Zhang,Jinjie Cui,Liming Cheng,Kaili Lin

Osteoporosis (OP) is a major systemic bone disease leading to an imbalance in bone homeostasis which remains a challenge in the current treatment of bone defects. Our previous studies on strontium (Sr) doping apparently stimulated osteogenesis of bioceramics, which suggested a promising strategy for the treatment of bone defects. However, the potential effects and the underlying mechanisms of Sr-doping on osteoporotic bone defects still remain unclear. Autophagy is a conventional self-degradation process of cells involved in bone homeostasis and regeneration under physiological and pathological conditions. Therefore, it is essential to design appropriate biomaterials and investigate the associated osteogenic mechanisms via autophagy. Based on this hypothesis, Sr-doped 45S5 bioglass (Sr/45S5) was fabricated, and ovariectomy bone marrow-derived mesenchymal stem cells (OVX-BMSCs) were applied as the in vitro cell culture model. First, the optimal Sr-doping concentration of 10 mol% was screened by cell proliferation, ALP staining, alizarin red S staining and the real-time PCR assay. Then, the results of western blot (WB) analysis showed that Sr-induced osteogenic differentiation of OVX-BMSCs was associated with time-dependent modulation of autophagy and related to the AKT/mTOR signaling pathway. Meanwhile, the autophagy in Sr-induced osteogenic differentiation of OVX-BMSCs was detected by WB, immunofluorescence staining and transmission electron microscopy. Furthermore, the effect of osteogenic differentiation of OVX-BMSCs has been significantly inhibited by the administration of autophagy inhibitors and the AKT/mTOR pathway inhibitors, respectively, in the early and late periods of osteogenic differentiation. Finally, the results of the model of femoral condyle defects in OVX-rats indicated that Sr10/45S5 granules remarkably enhanced bone regeneration which provided the evidences in vivo. Our research indicates that Sr-doping provides a promising strategy to promote osteogenic differentiation of OVX-BMSCs and bone regeneration in osteoporotic bone defects via early improvement of autophagy and late activation of the Akt/mTOR signaling pathway.

Emodin Ameliorates Renal Damage and Podocyte Injury in a Rat Model of Diabetic Nephropathy via Regulating AMPK/mTOR-Mediated Autophagy Signaling Pathway

Hong Liu,Quan Wang,Ge Shi,Wenqiang Yang,Yanmin Zhang,Weidong Chen,Sheng Wan,Fei Xiong,Zengsi Wang

Purpose The activation of autophagy has potential protective effect on diabetic nephropathy (DN) podocyte injury, and the AMPK/mTOR signaling pathway is an important regulatory pathway of autophagy. Emodin has been reported to effectively delay DN progression; however, the therapeutic mechanisms involved in vivo remain ambiguous. The present study aimed to elucidate the mechanism of emodin in improving renal tissue and podocyte injury in DN by regulating the AMPK/mTOR-autophagy signaling pathway. Methods All rats were divided into 4 groups: a Sham group, a Vehicle group, a low-dose emodin (LD-Emo) group (20 mg/kg/day) and a high-dose emodin (HD-Emo) group (40 mg/kg/day). The different doses of Emo and distilled water were daily administrated for 8 weeks after the induction of DN by the unilateral nephrectomy combined with intraperitoneal injections of streptozotocin (STZ). The rats' general status, blood glucose, biochemical parameters, urinary protein excretion, renal histological changes and cell apoptosis in renal tissue, as well as the key protein expressions in the AMPK/mTOR signaling pathway and apoptosis-related proteins were examined, respectively. Results Emodin ameliorated the general condition, kidney weight and urinary protein excretion of the rats, but has little influence on serum biochemical parameters and did not lower blood glucose; emodin attenuated renal fibrosis including the cell numbers, extracellular matrix rate and collagen area in glomerulus, simultaneously relieved podocyte foot process fusion, up-regulated the expression of nephrin protein and suppressed glomerular and tubular epithelial cell apoptosis. In addition, emodin can induce and enhance autophagy in podocytes including increased expression of LC3-II/I, Beclin-1, p-AMPK protein and decreased expression of p62, p-mTOR protein, as well as increased autophagosomes in podocytes. Conclusion We have demonstrated that emodin, as a natural regulator in vivo, reduced proteinuria and alleviated renal fibrosis without affecting hyperglycemia in DN rats. The potential mechanisms by which emodin exerts its renoprotective effects in vivo are through suppressing cell apoptosis and enhancing autophagy of podocytes via the AMPK/mTOR signaling pathway in the kidney.

Molybdenum and cadmium co-exposure induces CaMKKβ/AMPK/mTOR pathway mediated-autophagy by subcellular calcium redistribution in duck renal tubular epithelial cells

Ting Cui,Xueru Wang,Junyu Hu,Tianjin Lin,Zhisheng Hu,Huiling Guo,Gang Huang,Guoliang Hu,Caiying Zhang

Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants . Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca 2+ ) regulates autophagy is unclear. The results revealed that the Mo- and/or Cd-induced cytosolic Ca 2+ concentration ([Ca 2+ ] c ) increase mainly came from intracellular calcium stores. Mo and/or Cd caused mitochondrial Ca 2+ content ([Ca 2+ ] mit ) and [Ca 2+ ] c increase with endoplasmic reticulum (ER) Ca 2+ content ([Ca 2+ ] ER ) decrease and upregulated calcium homeostasis-related factor expression levels, but 2-Aminoethoxydiphenyl borate (2-APB) reversed subcellular Ca 2+ redistribution. Increased Phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP 3 ) activities and inositol 1,4,5-trisphosphate receptor (IP 3 R) expression level were observed in Mo- and/or Cd-treated cells, which was reversed by the PLC inhibitor U-73122. 2-APB and 1,2-Bis (2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) addition mitigated [Ca 2+ ] c and autophagy (variations in microtubule-associated protein light chain 3 (LC3), LC3B-II/LC3B-I, autophagy related 5 (ATG5), sequestosome-1(P62), programmed cell death-1 (Beclin-1) and Dynein expression levels, LC3 puncta, autophagosomes and acid vesicle organelles) under Mo and/or Cd treatment, respectively, while thapsigargin (TG) had the opposite impacts. Additionally, the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 reversed the increased CaMKKβ, adenosine 5′-monophosphate-activated protein kinase (AMPK), Beclin-1, and LC3B-II/LC3B-I protein expression levels and reduced mammalian target of rapamycin (mTOR) and P62 protein expression levels in Mo- and/or Cd-exposed cells. Collectively, the results confirmed that [Ca 2+ ] c overload resulted from PLC/IP 3 /IP 3 R pathway-mediated ER Ca 2+ release, and then activated autophagy by the CaMKKβ/AMPK/mTOR pathway in Mo- and/or Cd-treated duck renal tubular epithelial cells.

Polysaccharide from the seeds of Plantago asiatica L. alleviates nonylphenol induced reproductive system injury of male rats via PI3K/Akt/mTOR pathway

Fenfen Li,Danfei Huang,Weiyu Yang,Xiaozhen Liu,Shaoping Nie,Mingyong Xie

The preventive role of polysaccharide from the seeds of Plantago asiatica L. (PLCP) against reproductive system injury induced by nonylphenol (NP) was investigated. Male Sprague-Dawley rats were exposed orally to NP 1 h after PLCP intragastric administration continuously for 45 days. The results showed that NP induced significant decrease in relative weight of testes and epididymis, changed testicular histomorphology, and disrupted hormone secretions. Moreover, oxidative stress occurred after NP exposure by overproduction of Malondialdehyde, lipid peroxidation, inducible nitric oxide synthase, and low activities of superoxide dismutase and catalase. Furthermore, the induction of apoptosis and disturbance of PI3K/Akt/mTOR pathway by NP were also proved. Interestingly, PLCP alleviated NP toxicity by improving antioxidant enzymes, recovering hormone secretions, inhibiting apoptosis and autophagy, which involves PI3K/Akt/mTOR pathway. These findings provide a good direction that PLCP may be a good candidate to help body defend against toxic substance, particularly endocrine disrupting chemicals induced reproductive toxicity.